In order to assess the significance of activated oncogenes in the pathogenesis of human urological malignancies, fresh urothelial tumors of the bladder and kidney were screened by both DNA transfection and restriction size polymorphism analysis. The frequency of Ha-ras activation by point mutations at the 61st or 12th codons was estimated to be about 10%. No rearrangement of ras genes was detected. In one of 21 tumors, a 40-fold amplification of the Ki-ras gene was detected. Similar findings were made with fresh human renal cell carcinomas, suggesting the importance of quantitative as well as qualitative alterations of ras oncogenes in urological tumors. In nitrosamine-induced rat bladder tumors, activated Ha-ras was found in one of nine tumors by DNA transfection. The feasibility of this system as a model of human bladder carcinogenesis is being studied. Modification of the effect of activated ras oncogenes by anti-sense RNA or chemical mutagens is also being tried.